Pierre-Yves Ancel

Background: Population‐based data are needed to reliably assess the impact of SARS‐CoV‐2 infection during pregnancy.Objectives: To estimate the population‐based incidence of SARS‐CoV‐2 infection and its severe forms in the obstetric population, identify risk factors of severe SARS‐CoV‐2 infection (severe COVID‐19) and describe delivery, maternal and neonatal outcomes by disease severity, using a definition of severity based on organ dysfunction.Methods: A prospective population‐based study conducted over the three first pandemic waves between March 2020 and April 2021 in 281 maternity hospitals in six French regions included all women with SARS‐CoV‐2 infection during pregnancy or within 7 days post‐partum, whether symptomatic or not, hospitalised or not. Severe COVID‐19 forms were defined a priori using clinical, biological and management criteria of organ dysfunction. We calculated infection and severe infection rates and studied associations between sociodemographic, medical and pregnancy characteristics and severe COVID‐19 by univariate and multivariate modified Poisson regression modelling.Results: From a population of 385,214 deliveries in the participating regions, 6015 women with SARS‐CoV‐2 infection were identified, including 337 severe cases. The rates of severe COVID‐19 were 1.1, 0.9 and 3.6 per 1000 deliveries during the first, second and third pandemic waves, respectively, and the proportions of severe COVID‐19 were 8.6%, 3.4% and 9.3%, respectively. On multivariate analysis, the risk of severe COVID‐19 was associated with younger and older age, migrant status, living with > 4 people, overweight or obesity, chronic hypertension or diabetes and infection ≥ 22 weeks of gestation rather than earlier in pregnancy. Neonatal morbidity occurred mostly with severe maternal infection.Conclusion: Using an organ‐based definition of severity and population‐based data, rates of severe COVID‐19 appeared lower than in previous studies. A permanent perinatal surveillance system is needed to assess efficiently and rapidly the impact of future pandemics.

Background: The relationship between maternal obesity and childhood cognitive development remains unclear. Prior studies did not adjust for important confounders, and preterm infants are a developmentally distinct group that remains scarcely examined.Objectives: To determine whether maternal prepregnancy body mass index (BMI) is associated with offspring intelligence quotient (IQ) up to 5 years and whether this relationship varies with gestational age.Methods: Data from two French birth cohorts, EDEN (all gestational ages) and EPIPAGE‐2 (preterm children born between 24 and 34 weeks of gestation), were used for this study. Maternal prepregnancy weight and height were used to calculate prepregnancy BMI. The Wechsler Preschool and Primary Scale of Intelligence was used to assess child IQ around 5 years. Multivariable models were adjusted for confounders, including socioeconomic status and paternal BMI.Results: Analytical cohorts included 1100 children from EDEN and 2629 from EPIPAGE‐2. Lower intellectual functioning (full‐scale IQ < 85) was observed in 8.1% of children in EDEN and 19.6% in EPIPAGE‐2. The prevalence of maternal obesity was 13.6% (EDEN) and 21.3% (EPIPAGE‐2) among children with lower intellectual functioning compared to 8.9% (EDEN) and 12.9% (EPIPAGE‐2) among children with normal intellectual functioning. Maternal prepregnancy obesity was associated with an approximately 3‐point decrease in full‐scale IQ scores in fully adjusted models (adjusted β −2.8, 95% confidence interval [CI] −5.6, −0.1 and −2.6, 95% CI −4.7, −0.6 in EDEN and EPIPAGE‐2, respectively). In EDEN, maternal obesity was associated with lower scores in the verbal IQ domain. Among infants born preterm (EPIPAGE‐2), maternal obesity was associated with lower scores in the processing, reasoning, and verbal IQ domains. Adjustment for paternal BMI did not change the magnitude of the relationship with maternal obesity.Conclusions: High maternal prepregnancy BMI is associated with child cognitive development around 5 years of age.

Background: The life course of individuals born very premature is a topic of increasing concern. The association between high early amino acid intake and later high blood pressure (HBP) in preterm neonates is debated. Methods and Results: In a national, prospective, population‐based birth cohort, EPIPAGE‐2 (Etude Epidémiologique sur Petits Ages Gestationnels), we assessed blood pressure at 5 years. Eligible infants were those born between 24 and 29 weeks of gestation. Infants were distributed in 2 groups of 717 infants matched on propensity score on whether or not they were exposed to high amino acid intake (>3.5 g/kg per day at day 7); 455 control term infants were also enrolled. A value ≥95th percentile of reference values for age and height defined systolic or diastolic HBP. Blood pressure at 5 years of age was assessed for 389 and 385 children in the exposed and nonexposed groups, respectively. Rates (in percent) of systolic and diastolic HBP were 18.0% (95% CI, 14.5%–22.2% ) , 13.3% (95% CI, 10.3%–17.0%), 8.5% (95% CI, 6.5%–11.1%), and 9.0% (95% CI, 6.6%–12.3%), 10.2% (95% CI, 7.5%–13.6%), and 5.4% (95% CI, 3.8%–7.6%) in exposed, nonexposed, and term‐born groups, respectively. Exposure to high early amino acid intake and maximal serum creatinine (by 50 μmol/L) between day 3 and day 7 were 2 independent risk factors for systolic HBP (adjusted odds ratio [aOR], 1.60 [95% CI, 1.05–2.43] and aOR, 1.59 [95% CI, 1.12–2.26], respectively) but not for diastolic HBP (aOR, 0.84 [95% CI, 0.50–1.39] and aOR, 1.09 [95% CI, 0.71–1.67], respectively). After adjustment for 5‐year weight Z score, the aOR between high early amino acid intake and systolic HBP was 1.50 [95% CI, 0.98–2.30]. Conclusions: These results suggest that mechanisms of childhood systolic HBP involve neonatal renal challenge by high amino acid intake or dysfunction.

Children born very preterm may have neurobehavioral problems that impact school, family, social adjustments, and their adult lives.^1,2 Neurodevelopmental outcomes in these children are characterized by a set of developmental dysfunctions (eg, language, praxis, executive function [EF], attention, and behavioral disorders) that tend to accumulate and even potentiate each other.^3-6

Early life gut microbiota-influencing factors may play an important role in programming individuals long-term health and substantial efforts have been devoted into studying the development of the gut microbiota in relation to early life events. This study aimed to examine in a single study, the persistence of associations between 20 factors occurring in the early life and the gut microbiota at 3.5 years of 798 children from two French nationwide birth cohorts, EPIPAGE 2 (very preterm children) and ELFE (late preterm and full-term children). Gut microbiota profiling was assessed using 16S rRNA gene sequencing-based method. Upon thorough adjustment of confounding factors, we demonstrated that gestational age was one of the factors most associated with gut microbiota differences with a noticeable imprint of prematurity at 3.5 years of age. Children born by cesarean section harbored lower richness and diversity and a different overall gut microbiota composition independently of preterm status. Children who had ever received human milk were associated with a Prevotella-driven enterotype (P_type) compared to those who had never received human milk. Living with a sibling was associated with higher diversity. Children with siblings and those attending daycare centers were associated with a P_type enterotype. Maternal factors including the country of birth and preconception maternal body mass index were associated with some microbiota characteristics: children born to overweight or obese mothers showed increased gut microbiota richness. This study reveals that multiple exposures operating from early life imprint the gut microbiota at 3.5 years that is a pivotal age when the gut microbiota acquires many of its adult characteristics.

Objective: To evaluate, in very preterm infants, the hemoglobin (Hb) levels during the first 24 h and the neurodevelopment outcomes at 24 months of corrected age. Design, setting, and patients: We conducted a secondary analysis of the French national prospective and population-based cohort EPIPAGE-2. The eligible study participants were live-born singletons who were born before 32 weeks of gestational age, with early Hb levels who were admitted to the neonatal intensive care unit. Main outcome measures: The early Hb levels for an outcome survival at 24 months of corrected age without neurodevelopmental impairment were measured. The secondary outcomes were survival at discharge and without severe neonatal morbidity. Results: Of the 2158 singletons of 26 weeks with Hb of p < 0.01). Conclusions: Early low Hb levels are associated with major neonatal morbidities in VP singletons, but not with neurodevelopment outcomes at two years of age, except in male infants of >26 Weeks GA.

Objective To determine whether birth outside a level-3 centre (outborn) is associated with a difference in the combined outcome of mortality or moderate-to-severe neurological impairment at 5.5 years of age compared with birth in a level-3 centre (inborn) when antenatal steroids and gestational age (GA) are accounted for. Design Individual matched study nested within a prospective cohort. Each outborn infant was matched using GA and antenatal steroids with a maximum of four inborns. Conditional logistic regression was used to calculate ORs before being adjusted using maternal and birth characteristics. Analyses were carried out after multiple imputation for missing data. Setting EPIPAGE-2 French national prospective cohort including births up to 34 weeks GA inclusive. Patients Outborn and inborn control infants selected between 24 and 31 weeks GA were followed in the neonatal period and to 2 and 5.5 years. 3335 infants were eligible of whom all 498 outborns and 1235 inborn infants were included—equivalent to 2.5 inborns for each outborn. Main outcome measure Survival without moderate-to-severe neurodevelopmental impairment at 5.5 years. Results Chorioamnionitis, pre-eclampsia, caesarian birth and small-for-dates were more frequent among inborns, and spontaneous labour and antepartum haemorrhage among outborns. There was no difference in the main outcome measure at 5.5 years of age (adjusted OR 1.09, 95% CI 0.82 to 1.44); sensitivity analyses suggested improved outcomes at lower GAs for inborns. Conclusion In this GA and steroid matched cohort, there was no difference in survival without moderate-to-severe neurodevelopmental impairment to 5.5 years of age between inborn and outborn very preterm children. This suggests steroids might be important in determining outcomes.